The atypical antipsychotics constitute an important class of drugs for the treatment and prevention of psychotic disorders.
Such drugs were proposed as a means for overcoming the problems arising with the use of antipsychotics of the previous generation, namely, the typical antipsychotics, associated with major and severe side effects.
An example of an atypical antipsychotic agent with a favourable therapeutic application is to be found in the class of polycondensed heterocycles with a pyrrolo[2,1-b]benzothiazepine structure described in the international patent applications WO 00/06579 and WO 02/10175, both filed in the name of the present applicant. The first of these applications describes compounds in which, in the thiazepine ring, the bond between carbons 9 and 10 is saturated; conversely, in the second application said bond is unsaturated, and this latter class of compounds is also generically called “enamines”. Both classes of compounds have in common, at position 9, a group that can be selected from C1-C4 dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 4-alkyl-1-piperidinyl, and 4-alkyl-1-homopiperazinyl. Particularly preferred are compounds bearing, at position 9, one of the groups 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 4-alkyl-1-piperidinyl, 4-alkyl-1-homopiperazinyl, all commonly characterised by an alkyl group at position 4 of the heterocyclic ring.
In particular, the compound (S)(+) 7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, described in patent application WO 00/06579 and hereinafter referred to for short as ST1460, has demonstrated atypical antipsychotic properties comparable with those of the clinical reference compounds (clozapine and olanzapine) and is associated with lower risks of occurrence of extrapyramidal and/or neuroendocrine effects, characteristic of the typical antipsychotics.
The compound 9-(4-methylpiperazin-1-yl)-pyrrolo[2,1-b]-[1,3]benzothiazepine, described in patent application WO 02/10175 and hereinafter referred to in short as ST1899, also presents favourable pharmacological characteristics and affords the advantage, compared to the preceding compound, of greater activity and greater simplicity of synthesis.
Though endowed with a satisfactory pharmacological profile, the compounds described in the above-mentioned patent applications present kinetics calling for some improvement, in that they are characterised by rapid clearance. It is therefore desirable to have compounds with a similar, if not better, pharmacological profile, but most certainly with an improved pharmacokinetic profile.